Hydroxy thioaliphatic acids and methods of preparing the same



United States Patent HYDRoxY rrnoALrP A-Tic Acms AND lvmrrnonsonranmnme SAME .Milon W. Bullock, PearLRiVen-NJY assignorto American Cyanamid Company, .NewYork, N. Y., acorporation of Maine No Drawing. Application October 19, 19 53 Serial No. 387,026

10 Claims. .(Cl. 260-399) This invention relates to new organic compounds. More particularly, it relates to hydroxy thioaliphatic acids, esters and salts thereof and methods of preparing the same.

In my copending application, Serial Number 284,205, filed April 24, 1952, I describe the preparation of omega- {3 (1,2 dithiolamyl )]aliphatic acids, salts and esters in which R is hydrogen, lower alkyl, or alkali metal radical, R is hydrogen, alkyl, monocyclic aryl substituted lower alkyl or lower fatty acid acyl radical, R" is hydrogen or a lower alkyl-radical and n is a Whole number less than 7. In the above formula the alkyl radicals can be methyl, ethyl, propyl, butyl, isobutyl, amyl, and the like. The lower fatty acid acyl radicals can be acetyl, propionyl, butyryl, valeryl, etc.

The compounds of the present invention are, in general, liquids at room temperature. They are immiscible with water and soluble or miscible, in general, with organic solvents such as acetone, 'chloroform, ether, etc.

To prepare the compounds of the present invention it is preferred to reduce the thiosubstituted keto esters described and claimed in my copending application, Serial Number 387,025, filed October 19, 1953 with a reducing agent such assodium borohydride, lithium aluminum hydride, aluminum isopropylate, and the like.

The reaction to prepare the compounds of the present invention may be illustrated as follows:

in which R is hydrogen, lower alkyl, or alkali metalradical, R is hydrogen alkyl, monocyclic aryl substituted lower alkyl and lower fatty acid acyl radicals, R" is hydrogen or a lower alkyl radical and n is a whole number less than 7.

The reaction is preferably carried out in the presence of an alcohol such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol and the like. The reaction will usually take place at room temperature, however, temperatures of from to 85 C. can be used. Follow- 2,828,322 Patented -Mar. 25, 19518 ice ' free carboxylic acid radical and mercaptan group (-.-SH-) respectively. 'If desired, salts of the free carboxylic acid canbe prepared .by treatingthe same with alkali .metal or alkaline earth metal hydroxides and the like.

The following examples illustrate in greater particularity the preparation of the compounds of the present invention.

Example I To 8.0 g. (0.0435 mole) of ethyl A ,6-ketooctenoate contained in a 50 ml fiaskequipped with a condenser-was added 3.62 g. (0.048 mole) of thioacetic acid The reaction was rapid and exothermic. The excess .thioacetic acid was distilled off under the reduced pressure of an aspirator. The product'was taken up in methanol and 4 g. (large excess) of sodium borohydride was added in small portions. The reaction was left standing overnight. The solution was made strongly alkaline by the addition of 10 g. of KOH in 15 ml. of water and refluxed three hours. The methanol was distilled off and replaced by water. The aqueous solution was acidified and the product extracted with two 25 ml. portions of chloroform. The combined chloroform extracts were dried over sodium sulfate and distilled leaving 8.0 g. (0.0416 mole) of an almost colorless oil. Approximately 1 ml. of this oil was subjected to distillation under reduced pressure. The

product distilled 164 C. at 0.05 mm. and had equivalent weight 211 suggesting that the -8-thio56-hydroxyoctanoic acid partially lactonized on distillation.

Example 2 tion was added. An excess of sodium borohydride was now present. The solution was allowed to warm up to room temperature and the methanol distilled off. The syrupy residue was diluted with chloroform and then water. The chloroform which had a milky appearance was washed once with dilute sulfuric acid and dried over a mixture of sodium bicarbonate and sodium sulfate. Distillation of the chloroform solution left a thick oil containing some solid. Five ml. of water and '20 ml. of chloroform were added and the solvents distilled off under reduced pressure on the steam bath. The oily product, weight 77 g., was purified by distillation under reduced pressure. The fraction distilling 140-132 at 01-005 mm. was collected as product. The yield was 57.7 g. (0.220 mole), 62%. The pure material has N 1.4670 and d 1.055.

A solution of 11.0 g. (0.166 mole or potassium hydroxide in 40 ml. of water was added to 20 g. (0.0763 mole) of ethyl 8-acetylthio-6-hydroxyoctanoate. The reaction appeared to be exothermic and the second phase disappeared when the flask was shaken. The resulting solution was left standing thirty-six hours. The solution was diluted with 400 ml. of water and extracted with ml. of ether. Distillation of the either extract left 05 an .lected as follows:

g. of oilwhich was discarded. The aqueous solution was acidified with hydrochloric acid and extracted three times.

N 0. Boiling Pressure, Weight m, Neutral Point millimeters Equivalent Distilling residue 2. 5

Yield of all products distilling, g. (0.052 mole),

a mixture of the acid and its lactone. This was confirmed by infrared studies. I

- Example 3 Sixteen and four-tenths grams (0.067 mole of ethyl 7-acetylthio-5-ketoheptanoate were diluted .with 100 ml. of ethanol. The solution was stirred with a magnetic stirrer while a solution of l g. (0.027 mole) of sodium borohydride in 50 ml. of ethanol was added over a period of fifteen minutes. The reaction was slightly exothermic. A test for excess reducing agent was positive. The alcohol was distilled off on the steam bath, the major portion at atmospheric pressure and the last under slightly reduced pressure. Water was added to the residue and the product extracted with two 100 ml. portions of ether. The combined ether extracts were washed with 4 N sulfuric acid and with half-saturated sodium bicarbonate solution. Distillation of the dried (sodium sulfate) ether extracts left 13.5 g. of an oil. This oil was purified by vacuum distillation. The fraction distilling 108 110 at 0.04 mm. was collected as product. The yield of ethyl 7-acetylthio-S-hydroxyheptanoate was 11.3 g. (0.0455 mole), 68%. Thisproduct had 11 1.4800 and 71 1.090.

Example 4 In a 500 ml. two-neck flask were placed 52.5 g. (0.191 I mole) of ethyl 8-acetylthio-6-ketonon-anoate and 150 ml. of distilled ethanol. The reaction mixture was stirred with a magnetic stirrer while a solution of 3.8 g. (0.0955 mole as 95%) sodium borohydride was added over a period of fifteen minutes. The temperature of the reaction mixture rose to about 70 from the heat of reaction. A test for excess reducing agent waspositive. The ethanol was distilled off on the steam bath, first at atmospheric pressure and finally under reduced pressure. The residue was diluted with 200 ml. of ether and a} solid filtered ofr". The ether solution was washedwith water, with dilute sulfuric acid and dried over sodium sulfate containing a small amount of sodium bicarbonate. Distillation of the ether solution gave 44 g. of a yellow oil which was purified by two distillations to yield 29.0 g. (0.105 mole), 55% of ethyl 8-acetylthio-6-hydroxynonanoate, boiling point 108-l09 at 0.05 mm., n 1.4678, (1' 1.036;

Example 5 In a 500 ml..stillpot wereplaced 4.0.0 g. 044511 016 of ethyl 8-acetylthio-6 ketononanoate and 200 ml. of dry isopropanol containing 37.4 g. (0.183 mole) of distilled aluminum isopropylate. -The resulting solution was refluxed through an effici ent column and acetone was taken off at the top. After six hours an additional 20 g. (0.098 mole) of aluminum isopropylate in 100 ml. of iso propanol were added; After an additional hour a test for acetone in the distillate showed thatthe reaction was nearing completion. After refluxing overnight only a. very small amount of acetone could be obtained indicating that the reduction was complete. Most of the solvent was distilled off and the residue shaken with 500 ml. of cold 1:4 hydrochloric acid. The product was extracted with two ml. portions of chloroform. The combined chloroform extracts were washed with dilute hydrochloric acid, half-saturated sodium bicarbonate solu tion and dried over sodium sulfate. Distillation of the solvent left an oil which was purified by vacuum distillation. The product, ethyl 8-acetylthio-6-hydroxynonanoate, distilled 111115 at 0.04 mm. The yield was 29.1 g. (0.1055 mole), 72.5%. The product from this reduction had n 1.4714 and d 1.010.

Example 6 In a 500 ml. three-neckflask equipped with stirrer, condenser and droppingfunnel were placed 73 g. (0.236 mole) of ethyl S-benzylthio-6-ketooctanoate and 250 ml. distilled ethanol. A solution of 9.4 g. (0.236 mole) of sodium borohydride in 50 ml. alcohol was added over a period of tenmihutes. The slightly exothermic reaction was stirred one hour andithe solvent distilled 011 ,on the steam cone. The residue was triturated with 200 ml. of water and theproduct extracted with two 100 ml. portions of ether. The combined ether extracts were washed with sodium bicarbonate solution, dried over sodium su1- fate and distilled. The oily residue was purified by vacuum distillation. The fraction distilling 184200 at 0.1 mm. was collected as product. The yield was 39 g. (0.125 mole), 53%. t A sample was redistilled to obtain an analytical sample. The purified material, ethyl 8-benzylthio-6-hydroxyoctanoate, boiling point 196 at 0.05 mm. andhad n 1.5313 and d 1.076.

1. Compounds having the formula:

I: s ss sfiisaw i R SR1 on in which R is a member of the group consisting of hydrogen, benzyl, and an acetyl radical and R is a member of the group consisting of hydrogen and a lower alkyl radical. 2. Compounds having the formula; i

.QH omomonomomomomooR s o om on V in which R is a lower alkyl radical.

3. 8-thiol-6-hydroxyoctanoic acid. 7 V

4. Ethyl 8-acetylthio-6 hydroxyoctanoate.

5. Ethyl 8-benzylthio-6-hydroxyactanoate.

6. A method of preparing '8-thiol-6-hydroxyoctanoic acid which coniprisesreacting ethylS-acetylthio-6-ketooctanoate with sodium borohydride and subsequently with an alkali metal hydroxide and acidifying the resulting product} V 7. A methodof preparing compounds having the general formula 7 i Y acting a compound having the formula:

in which R is as defined above, with sodium borohydride and recovering said product therefrom.

8. A method of preparing compounds having the general formula:

0 omorncnomomomomr'i-on SR1 OH in which R is a member of the group consisting of hydrogen, benzyl, and an acetyl radical and R is a member of the group consisting of hydrogen and lower alkyl radicals which comprises reacting a compound having the formula in which R and R are as defined above with a member of the group consisting of sodium borohydride, aluminum isopropylate, and lithium aluminum hydride and recovering said compound therefrom.

9. A method of preparing ethyl S-acetylthio-G-hydroxyoctanoate which comprises reacting ethyl 8-acety1thio-6- ketooctanoate with sodium borohydride.

10. A method of preparing ethyl 8-benzylthio-6-hydroxyoctanoate which comprises reacting ethyl 8-benzy1thio- 6-ketooctanoate with sodium borohydride.

References Cited in the file of this patent UNITED STATES PATENTS McCool Sept. 18, 1951 Starker et a1. Aug. 14, 1956 OTHER REFERENCES 

1. COMPOUNDS HAVING THE FORMULA: 